Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing.
Miltefosine (MF) is the first oral compound used in the chemotherapy against leishmaniasis. Since the mechanism of action of this drug and the targets of MF in Leishmania are unclear, we generated in a step-by-step manner Leishmania major promastigote mutants highly resistant to MF. Two of the mutan...
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ftdoajarticles:oai:doaj.org/article:eef6be33d6e242d1b1f684f342ca5063 2023-05-15T15:07:55+02:00 Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. Adriano C Coelho Sébastien Boisvert Angana Mukherjee Philippe Leprohon Jacques Corbeil Marc Ouellette 2012-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0001512 https://doaj.org/article/eef6be33d6e242d1b1f684f342ca5063 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3279362?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001512 https://doaj.org/article/eef6be33d6e242d1b1f684f342ca5063 PLoS Neglected Tropical Diseases, Vol 6, Iss 2, p e1512 (2012) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2012 ftdoajarticles https://doi.org/10.1371/journal.pntd.0001512 2022-12-30T21:58:07Z Miltefosine (MF) is the first oral compound used in the chemotherapy against leishmaniasis. Since the mechanism of action of this drug and the targets of MF in Leishmania are unclear, we generated in a step-by-step manner Leishmania major promastigote mutants highly resistant to MF. Two of the mutants were submitted to a short-read whole genome sequencing for identifying potential genes associated with MF resistance.Analysis of the genome assemblies revealed several independent point mutations in a P-type ATPase involved in phospholipid translocation. Mutations in two other proteins-pyridoxal kinase and α-adaptin like protein-were also observed in independent mutants. The role of these proteins in the MF resistance was evaluated by gene transfection and gene disruption and both the P-type ATPase and pyridoxal kinase were implicated in MF susceptibility. The study also highlighted that resistance can be highly heterogeneous at the population level with individual clones derived from this population differing both in terms of genotypes but also susceptibility phenotypes.Whole genome sequencing was used to pinpoint known and new resistance markers associated with MF resistance in the protozoan parasite Leishmania. The study also demonstrated the polyclonal nature of a resistant population with individual cells with varying susceptibilities and genotypes. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 6 2 e1512 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Adriano C Coelho Sébastien Boisvert Angana Mukherjee Philippe Leprohon Jacques Corbeil Marc Ouellette Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Miltefosine (MF) is the first oral compound used in the chemotherapy against leishmaniasis. Since the mechanism of action of this drug and the targets of MF in Leishmania are unclear, we generated in a step-by-step manner Leishmania major promastigote mutants highly resistant to MF. Two of the mutants were submitted to a short-read whole genome sequencing for identifying potential genes associated with MF resistance.Analysis of the genome assemblies revealed several independent point mutations in a P-type ATPase involved in phospholipid translocation. Mutations in two other proteins-pyridoxal kinase and α-adaptin like protein-were also observed in independent mutants. The role of these proteins in the MF resistance was evaluated by gene transfection and gene disruption and both the P-type ATPase and pyridoxal kinase were implicated in MF susceptibility. The study also highlighted that resistance can be highly heterogeneous at the population level with individual clones derived from this population differing both in terms of genotypes but also susceptibility phenotypes.Whole genome sequencing was used to pinpoint known and new resistance markers associated with MF resistance in the protozoan parasite Leishmania. The study also demonstrated the polyclonal nature of a resistant population with individual cells with varying susceptibilities and genotypes. |
format |
Article in Journal/Newspaper |
author |
Adriano C Coelho Sébastien Boisvert Angana Mukherjee Philippe Leprohon Jacques Corbeil Marc Ouellette |
author_facet |
Adriano C Coelho Sébastien Boisvert Angana Mukherjee Philippe Leprohon Jacques Corbeil Marc Ouellette |
author_sort |
Adriano C Coelho |
title |
Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
title_short |
Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
title_full |
Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
title_fullStr |
Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
title_full_unstemmed |
Multiple mutations in heterogeneous miltefosine-resistant Leishmania major population as determined by whole genome sequencing. |
title_sort |
multiple mutations in heterogeneous miltefosine-resistant leishmania major population as determined by whole genome sequencing. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doi.org/10.1371/journal.pntd.0001512 https://doaj.org/article/eef6be33d6e242d1b1f684f342ca5063 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 6, Iss 2, p e1512 (2012) |
op_relation |
http://europepmc.org/articles/PMC3279362?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001512 https://doaj.org/article/eef6be33d6e242d1b1f684f342ca5063 |
op_doi |
https://doi.org/10.1371/journal.pntd.0001512 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
6 |
container_issue |
2 |
container_start_page |
e1512 |
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1766339349399470080 |